New insights into the formation and resolution of ultra-fine anaphase bridges

Chan, Kok Lung; Hickson, Ian D.

doi:10.1016/j.semcdb.2011.07.001

Cited by 95 publications

(111 citation statements)

References 50 publications

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“…BLM-stained DAPI bridges link centromeric DNA BLM-positive anaphase bridges are commonly classified into (1) centromeric bridges that contain unresolved fully replicated DNA catenanes or (2) FANCD2/FANCIassociated bridges, which localize to chromosome arms (at loci representing common fragile sites) and mostly contain DNA replication intermediates (Chan et al 2007(Chan et al , 2009Naim and Rosselli 2009;Chan and Hickson 2011). We therefore examined whether the DAPI-positive bridges observed in resolvase-depleted cells were primarily centromeric or FANCD2-associated.…”

Section: Resultsmentioning

confidence: 99%

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Davies²,

2014

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The resolution of recombination intermediates containing Holliday junctions (HJs) is critical for genome maintenance and proper chromosome segregation. Three pathways for HJ processing exist in human cells and involve the following enzymes/complexes: BLM-TopoIIIa-RMI1-RMI2 (BTR complex), SLX1-SLX4-MUS81-EME1 (SLX-MUS complex), and GEN1. Cycling cells preferentially use the BTR complex for the removal of double HJs in S phase, with SLX-MUS and GEN1 acting at temporally distinct phases of the cell cycle. Cells lacking SLX-MUS and GEN1 exhibit chromosome missegregation, micronucleus formation, and elevated levels of 53BP1-positive G1 nuclear bodies, suggesting that defects in chromosome segregation lead to the transmission of extensive DNA damage to daughter cells. In addition, however, we found that the effects of SLX4, MUS81, and GEN1 depletion extend beyond mitosis, since genome instability is observed throughout all phases of the cell cycle. This is exemplified in the form of impaired replication fork movement and S-phase progression, endogenous checkpoint activation, chromosome segmentation, and multinucleation. In contrast to SLX4, SLX1, the nuclease subunit of the SLX1-SLX4 structure-selective nuclease, plays no role in the replication-related phenotypes associated with SLX4/MUS81 and GEN1 depletion. These observations demonstrate that the SLX1-SLX4 nuclease and the SLX4 scaffold play divergent roles in the maintenance of genome integrity in human cells.

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Section: Resultsmentioning

confidence: 99%

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Davies²,

2014

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“…The appearance of anaphase bridges in BJ-LT cells prompted us to investigate the presence of another type of bridge, known as "ultrafine bridges" (UFBs) (62)(63)(64)(65). UFBs cannot be stained by conventional DNA dyes, although fluorescence in situ hybridization and bromodeoxyuridine (BrdU) incorporation indicate that they contain DNA.…”

Section: Resultsmentioning

confidence: 99%

Replication Stress and Mitotic Dysfunction in Cells Expressing Simian Virus 40 Large T Antigen

Filippakis

Huang

et al. 2013

J Virol

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cWe previously demonstrated that simian virus 40 (SV40) large T antigen (LT) binds to the Bub1 kinase, a key regulator of the spindle checkpoint and chromosome segregation. Bub1 mutations or altered expression patterns are linked to chromosome missegregation and are considered to be a driving force in some human cancers. Here we report that LT, dependent on Bub1 binding, causes micronuclei, lagging chromatin, and anaphase bridges, which are hallmarks of chromosomal instability (CIN) and Bub1 insufficiency. Using time-lapse microscopy, we demonstrate that LT imposes a Bub1 binding-dependent delay in the metaphase-to-anaphase transition. Kinetochore fibers reveal that LT, via Bub1 binding, causes aberrant kinetochore (KT)-microtubule (MT) attachments and a shortened interkinetochore distance, consistent with a lack of tension. Previously, we showed that LT also induces the DNA damage response (DDR) via Bub1 binding. Using inducible LT cell lines, we show that an activated DDR was observed before the appearance of anaphase bridges and micronuclei. Furthermore, LT induction in serum-starved cells demonstrated ␥-H2AX accumulation in cells that had not yet entered mitosis. Thus, DDR activation can occur independently of chromosome segregation defects. Replication stress pathways may be responsible, because signatures of replication stress were observed, which were attenuated by exogenous supplementation with nucleosides. Our observations allow us to propose a model that explains and integrates the diverse manifestations of genomic instability induced by LT.

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“…Subsequently, studies have shown that there are at least two different classes of UFBs (reviewed by Chan and Hickson 2011). The first class is derived primarily from centromeres whose resolution is delayed until anaphase onset (Fig.…”

Section: Resolving and Segregating Difficult Regions Of Chromosomesmentioning

confidence: 99%

Chromosome Dynamics during Mitosis

Hirano

2015

Cold Spring Harb Perspect Biol

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The primary goal of mitosis is to partition duplicated chromosomes into daughter cells. Eukaryotic chromosomes are equipped with two distinct classes of intrinsic machineries, cohesin and condensins, that ensure their faithful segregation during mitosis. Cohesin holds sister chromatids together immediately after their synthesis during S phase until the establishment of bipolar attachments to the mitotic spindle in metaphase. Condensins, on the other hand, attempt to "resolve" sister chromatids by counteracting cohesin. The products of the balancing acts of cohesin and condensins are metaphase chromosomes, in which two rod-shaped chromatids are connected primarily at the centromere. In anaphase, this connection is released by the action of separase that proteolytically cleaves the remaining population of cohesin. Recent studies uncover how this series of events might be mechanistically coupled with each other and intricately regulated by a number of regulatory factors.

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New insights into the formation and resolution of ultra-fine anaphase bridges

Cited by 95 publications

References 50 publications

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Roles of SLX1–SLX4, MUS81–EME1, and GEN1 in avoiding genome instability and mitotic catastrophe

Replication Stress and Mitotic Dysfunction in Cells Expressing Simian Virus 40 Large T Antigen

Chromosome Dynamics during Mitosis

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